The intracellular second messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), play a key role in signal transductions involving a myriad of processes in the central nervous system (CNS), immune system, and cardiovascular system. Cyclic nucleotide phosphodiesterases (PDEs) constitute a superfamily of enzymes that degrade cAMP and cGMP to regulate the functions of these second messengers. Among the 11 PDE subfamilies (PDE1-11), the cAMP-specific PDE7 isozyme is sub-divided into PDE7A (three variants) and PDE7B (four variants). In terms of organs, PDE7 variants are expressed in the brain and heart, followed by liver, skeletal muscles, kidneys, testes, pancreas, and in a variety of inflammatory and immune cells. Due to the broad expression and high substrate affinity of PDE7, regulation of its activity is essential for maintaining a precise narrow range of intracellular cAMP levels for normal physiological function. Consequently, the ability to clinically inhibit PDE7 action has emerged as a promising therapeutic strategy for a variety of neurological, inflammatory, and immunological disorders. Therefore, in order to promote the development of PDE7 inhibitors and facilitate diagnosis of PDE7-related diseases, we developed a PDE7 PET radioligand suitable for non-invasive tracking the location and concentration of PDE7 in vivo. We used a three-step synthetic approach involving urea formation via condensation between aniline and potassium isocyanate, followed by ring-closure with cyclohexanone and demethylation, to generate the target molecule PDE7-136 (IC50 PDE7A1 = 14 nM) and the corresponding demethylated precursor for carbon-11 labeling. We also performed molecular docking studies to investigate ligand-protein interactions. Further, we achieved carbon-11 labeling via methylation on the phenol precursor using [11C]iodomethane in the presence of potassium carbonate. The injection solution [11C]PDE7-136 in saline exhibited excellent radiochemical purity and high molar activities in a decay-corrected radiochemical yield of 19% relative to [11C]CO2 at the end of bombardment. The performance of [11C]PDE7-136 to penetrate the blood-brain barrier was verified by microPET imaging and biodistribution ex vivo. Further validation by in vitro autoradiography, radiometabolite analysis and microPET imaging in nonhuman primates is underway and will be discussed herein.

Radiosynthesis and preclinical evaluation of a carbon-11 labeled PDE7 inhibitor for PET neuroimaging

ACS Fall 2021

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